Voltage-gated sodium (Nav) channels are present in neurons and excitable tissues where they contribute to processes such as membrane excitability and muscle contraction (Ogata et al., Jpn. J. Pharmacol. (2002) 88(4) 365-77). Nine different transmembrane α-subunits (Nav1.1-1.9) from a single Nav1 family combine with auxiliary β-subunits that modify channel function to form functional Nav channels. Of the nine Nav1 α-subunit isoforms, five are expressed in the dorsal root ganglion where they are involved in setting the resting membrane potential and the threshold for generating action potentials, and also contribute to the upstroke as well as firing of action potentials during sustained depolarization. In particular, the tetrodotoxin (TTX) sensitive Nav1.7 and TTX-insensitive Nav1.8 channel subtypes act as major contributors to both inflammatory and neuropathic pain (Momin et al., Curr Opin Neurobiol. 18(4):383-8, 2008; Rush et al., J Physiol. 579(Pt 1):1-14, 2007).
Calcium channels mediate a variety of normal physiological functions and are also implicated in a number of human disorders. Examples of calcium-mediated human disorders include but are not limited to congenital migraine, cerebellar ataxia, angina, epilepsy, hypertension, ischemia, and some arrhythmias (see, e.g., Janis et al., Ion Calcium Channels: Their Properties, Functions, Regulation and Clinical Relevance (1991) CRC Press, London). T-type, or low voltage-activated, channels describe a broad class of molecules that transiently activate at negative potentials and are highly sensitive to changes in resting potential and are involved in various medical conditions. For example, in mice lacking the gene expressing the 3.1 subunit, resistance to absence seizures was observed (Kim et al., Mol Cell Neurosci 18(2): 235-245, 2001). Other studies have also implicated the 3.2 subunit in the development of epilepsy (Su et al., J Neurosci 22: 3645-3655, 2002).
Novel allosteric modulators of the slow-inactivation sodium or the slow-inactivation calcium channel are thus desired. Modulators may affect the kinetics and/or the voltage potentials of the slow-inactivation of one or any combination of Nav1.7, Nav1.8 or Cav3.2 channels.